1. Field of the Invention
The present invention relates to steroidal mixed tetraoxanes and to processes for the production thereof. In a preferred embodiment, the present invention relates to cycloalkyl-spiro-1,2,4,5-tetraoxacyclohexane-spiro-cholic acids and derivatives thereof, which are active against chloroquine-resistant malaria. The present invention also relates to gem-dihydroperoxides of cholic acids and derivatives thereof, and 1,1-dihydroperoxy(susbstituted)cycloalkanes.
2. Description of the Related Art
The current global situation with respect to malaria indicates that about two billion people are exposed to the disease and of these 400 million people are already infected. See Trigg, P. I., and A. V. Kondrachine (1998) The Current Global Malaria Situation, Chapter 2, p. 11-22, in MALARIA PARASITE BIOLOGY, PATHOGENESIS AND PROTECTION. Ed. I. W. Sherman, ASM Press, Washington, D.C. Each year between 100 to 200 million new cases of infection are reported and approximately 1 to 2 million people die due to malaria. The situation is rapidly worsening mainly due to non-availability of effective drugs and development of drug resistance of a large number of non-immune people in areas where malaria is frequently transmitted. See White, N. J. (1998) Br. Med. Bull. 54:703-715.
In an increasingly wide geographic area, both Plasmodium falciparum and Plasmodium vivax have been developing resistance to chloroquine, the most successful antimalarial drug in the past several decades. Mefloquine and doxycycline, the two other frontline drugs for the treatment and prevention of malaria are becoming increasingly ineffective. See Vroman, J. A. et al. (1999) Curr. Pharm. Design 5:101-138. Artemisinin analogs such as artesunate and arteether were later introduced that are found to be quite effective, particularly against drug-resistant P. falciparum but observations of drug-induced and dose-related neurotoxicity in animals have raised concern about the safety of these compounds for human use. See Bhattachajee, A. K. and J. M. Karle (1999) Chem. Res. Toxicol. 12: 422-428.
1,2,4,5-tetraoxane compounds have been found to exhibit antimalarial activity. See Vennerstrom, J. L., et al. (1992) J. Med. Chem. 35:3023-3027, WO93/07119, and Todorović, N. M., et al. (1996) Steroids 61:688-696. Unfortunately, the 1,2,4,5-tetraoxane compounds of the prior art are made by timely, complicated, and expensive methods, and also exhibit poor solubility under physiological conditions.
Therefore, a need still exists for a new class of tetraoxane compounds and compositions that may be used for treating, preventing, or inhibiting malaria and drug resistant malaria.